ABSTRACT Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States. Despite recent advances in understanding of aberrantly functioning signaling pathways involved in lung cancer development, the master regulator transcription factors affected by these altered signaling pathways that regulate the expression of critical genes involved in the growth and survival of lung cancer cells are still poorly understood. The transcription factor cyclic adenosine 3',5'- monophosphate-response element-binding protein (CREB) regulates the expression of numerous genes involved in cancer development and has been shown to play an important role in the proliferation, survival, and differentiation of several cell types. Recently, we found that CREB plays a role in the transdifferentiation and maintenance of the normal mucociliary phenotype of bronchial epithelial cells. In addition, CREB was expressed at significantly higher levels and more active in several non-small cell lung cancer (NSCLC) cell lines than in primary normal human tracheobronchial epithelial cells and in human lung squamous cell carcinoma and adenocarcinoma tissue than in paired adjacent normal lung tissue. Retrospective survival- duration analysis of patients with NSCLC showed that overexpression of the active form of CREB was a negative prognostic factor. Moreover, we observed that treatment with genetic and chemical inhibitors that blocked the expression and activation of CREB dramatically suppressed the growth and survival of NSCLC cells. In summary, our preliminary findings suggest that CREB is a critical molecule that controls both the normal differentiation of bronchial epithelial cells and the abnormal growth of lung cancer cells. Based on our findings, we hypothesize that aberrantly regulated CREB plays a critical role in the abnormal proliferation and survival of NSCLC cells. To test this hypothesis, we will pursue three specific aims: 1. To determine whether CREB promotes the pathogenesis of NSCLC by analyzing preneoplastic NSCLC lesions and modulating CREB expression and activity in an in vitro lung carcinogenesis model cell and in vivo animal models. 2. To identify the biologic and molecular consequences of modulating CREB activity using small molecule inhibitors in lung cancer development. 3. To establish the genetic role of CREB in the development of lung cancer. These studies will increase our understanding of the mechanisms of abnormal survival and proliferation of NSCLC cells, in particular, the role of CREB in lung cancer development. We are hopeful that this study will identify a novel target for preventive and/or therapeutic strategies in patients with NSCLC.